Proton Transfer Reaction—Mass Spectrometry (PTR-MS) is a well established method for chemical ionization, detection and quantification of (trace) compounds. An overview of the theoretical background and common applications is given e.g. in A. M. Ellis, C. A. Mayhew; Proton Transfer Reaction Mass Spectrometry Principles and Applications; John Wiley & Sons Ltd., UK, 2014. Advantages of this technique are high sensitivity, high selectivity, on-line quantification, direct sample injection and short response times. Although most common PTR-MS instruments employ proton transfer from H3O+ to the analytes, the technology is by no means limited to this form of ionization. Several instruments have been introduced, which enable the use of NO+, O2+, Kr+ and any other type of positively or negatively charged reagent ions for chemical ionization. Accordingly PTR-MS devices may also be called ion-molecule-reaction-mass spectrometry (IMR-MS) devices. Both terms PTR-MS and IMR-MS are used synonymously throughout this specification.
As for most analytical instrumentation also in IMR-MS there has always been a quest for improving the instrumental sensitivity. A higher sensitivity does not only mean that lower compound concentrations can be detected, i.e. that the limit-of-detection is improved, but also, that less measurement time is needed to acquire high quality data. For nearly 20 years sensitivity improvements were mainly achieved by optimizing the established instrumental design (e.g. design of transfer lens systems, vacuum system, ion source, etc.), while no fundamentally new developments were implemented in the reaction region. That is, even though a (commercial) IMR-MS instrument from 2009 might have orders of magnitude higher sensitivity than an instrument from 1999, the measurement results are virtually identical in terms of branching ratios and quantification results, because the fundamental ionization conditions have not changed.
However, it seems that the potential of optimizing the IMR-MS setup has been fully exploited at some point, so that the introduction of novel sensitivity improving measures became necessary. One common characteristic of nearly all recent attempts to improve sensitivity is the implementation of temporally changing electromagnetic fields (e.g. via AC, or more specifically RF (radio frequency) devices, like ion funnels, multipoles, helices, etc.—here referred to as RF devices—to guide ions into, within and/or out of the reaction region, i.e. installing RF devices in a region of the IMR-MS instrument, where the mean free path of the particles is small enough so that ion-molecule interactions involving analytes can take place. In the following such a “next generation” instrument will be referred to as an “RF/IMR-MS” instrument, whereas an instrument without such an RF device will be referred to as a “classic IMR-MS” instrument. One of the first studies on an RF/IMR-MS instrument has been published by S. Barber, R. S. Blake, I. R. White, P. S. Monks, F. Reich, S. Mullock, A. M. Ellis, Increased Sensitivity in Proton Transfer Reaction Mass Spectrometry by Incorporation of a Radio Frequency Ion Funnel. Analytical Chemistry 84 (2012) 5387-5391. Their aim was to considerably reduce the ion losses that inevitably occur at the exit aperture of the drift tube. Thus, they constructed a drift tube with an implemented ion funnel, i.e. the first half of the drift tube consisted of stainless steel plates with constant orifice diameters in the cm region, whereas the second half had plates with successively decreasing orifice diameters down to the mm region at the final plate. When applying an RF voltage in addition to the DC voltage, the second half acted as an ion funnel (see U.S. Pat. No. 6,107,628) and focused the ions into the mass spectrometer. Barber et al. demonstrated that the RF ion funnel increased the sensitivity of some compounds by a factor of 200 and more.
Another example of a sensitivity improving RF device in a IMR-MS instrument has been published by Sulzer et al. in 2014 (P. Sulzer, E. Hartungen, G. Hanel, S. Feil, K. Winkler, P. Mutschlechner, S. Haidacher, R. Schottkowsky, D. Gunsch, H. Seehauser, M. Striednig, S. Jürschik, K. Breiev, M. Lanza, J. Herbig, L. Märk, T. D. Märk, A. Jordan, A Proton Transfer Reaction-Quadrupole interface Time-Of-Flight Mass Spectrometer (PTR-QiTOF): High speed due to extreme sensitivity; International Journal of Mass Spectrometry 368 (2014) 1-5). They used a IMR-MS instrument with a quadrupole ion guide in the transfer region between the drift tube and the mass spectrometer in order to focus the ions and reduce ion losses in this region. An increase in sensitivity by a factor of 25 has been reported for this instrumental setup. Furthermore, the introduction of a quadrupole ion guide had a positive effect on the injection conditions into the mass spectrometer, which resulted in a considerable increase of mass resolution.
A third example is given in WO 2015/024033 wherein the whole reaction region is enclosed by electrodes which are in the form of helices and which replace the common stainless steel rings of the IMR-MS drift tube. (Varying) RF voltages are applied to these electrodes. One of the main advantages of the introduced setup is that it is capable of considerably increasing the instrumental sensitivity.
Besides these three examples, any other types of RF devices (e.g. multipoles, combinations of ion funnels and multipoles, etc.), any positions (e.g. beginning of the reaction region, replacing or complementing the drift tube, end of the reaction region) and any combinations could lead to performance improvements. However, all embodiments of an RF/IMR-MS instrument share one crucial disadvantage: The E/N of the reaction region cannot be calculated by simply dividing equation (1) by equation (2) anymore (see below), as at least some ion-molecule reactions take place in the RF device.
Barber et al. address this issue in their 2012 publication: “ . . . E/N of a combined ion funnel/drift tube, with its contribution from both dc and ac electric fields, is no longer obvious.” As a solution they suggest the introduction of the empirical parameter “effective E/N”. The concept behind this parameter is, that the reaction region is operated in DC only mode, i.e. in the classic mode where the E/N can be easily calculated, and the ratio between the reagent ions H3O+ and H3O+(H2O) is obtained at 10 different E/N settings within a reasonable E/N range (about 65 to 165 Td). Subsequently, the reaction region is switched to RF mode and the authors approximate the H3O+ to H3O+(H2O) ratios obtained in DC only mode by adjusting the peak-to-peak amplitude of the AC voltage, while keeping the DC voltage applied to the drift tube constant at 100 V. Finally, they assign those RF mode settings resulting in H3O+ to H3O+(H2O) ratios comparable to a corresponding E/N in DC only mode, the DC only mode E/N and denominate this value as “effective E/N”.
For other types of RF/IMR-MS instruments, there are no concepts to overcome the problem of unknown E/N other than claiming the contribution of the RF device on E/N was minor and could be neglected. Additionally, there are no concepts to overcome the problem for reagent ion different to H3O+.